Dialkylaminoalkyl 1-oxo-2alpha, 3, 4, 5-tetrahydroacenaphthen-2alpha-carboxylates



United States Patent 3,391,178 DIALKYLAMINOALKYL 1-0X0-2a,3,4,5-TETRAHY- DROACENAPHTHEN-Za-CARBOXYLATES Ernest E. Campaigne, 1240 E. Wylie St., Bloomington, Ind. 47401; Wendell Lee Roelofs, 71 Grove St., Apt. 10, Arlington, Mass. 02351; and Richard F. Weddleton, Evermann Apts., 463, Bloomington, Ind. 47401 No Drawing. Filed Dec. 30, 1964, Ser. No. 422,399 4 Claims. (Cl. 260-469) ABSTRACT OF THE DISCLOSURE 2a,3,4,S-tetrahydroacenaphthen 1 ones exhibit central nervous system depressant activity and are useful as antic-onvulsants and sedatives.

This invention relates to novel compounds. More particularly, this invention relates to novel substituted tetrahydroacenaphthenones which possess central nervous system depressant activity, and to a process for the preparation thereof. In another aspect, this invention relates to a novel method of depressing the central nervous system.

It is an object of the present invention to provide a new class of chemical compounds. It is another object of the present invention to provide novel compounds having central nervous system depressant activity, and a process for the preparation thereof. It is a further object of the present invention to provide a novel method of depressing the central nervous system.

These and other objects which may appear as the specification proceeds are achieved by this invention which comprises the provision of compounds selected from the group consisting of compounds having the following formula and the pharmaceutically acceptable nontoxic salts thereof. In Formula I,

R is a member selected from the group consisting of hydrogen, chloro, bromo, iodo, fluoro, trifluoromethyl, (lower)alkyl, (lower)alkoxy, (lower) alkanoyl, and (lower) alkanoyloxy; and

R is a member selected from the group consisting of cyano and a radical having the formula (II) 0 R wherein R and R each represent a member selected from the group consisting of (lower)alkyl, (lower)alkenyl, (lower)alkynyl, phenyl(lower) alkyl, cycloalkyl radicals having from 3 to 7 carbon atoms inclusive, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and when taken together with constitute a heterocyclic ring selected from the group consisting of pyrrolidino, (lower)alkylpyrrolidino, piperidino, (lower)alkylpiperidino, morpholino, (lower)alkylmorpholino, 1,2,5,6-tetrahyd-ropyridino, (lower)alkyl- 1,2,5,6 tetrahydropyridino, N (lower) alkylpiperazino,

3,391,178 Patented July 2, 1968 N (lower)alkyl (lower)alkylpiperazino, hexamethyleneimino and (lower)alkylhexamethyleneimino; and Y is a (lower)alkylene radical having from 1 to 8 carbon atoms, e.g. methylene, ethylene, propylene, isopropylene, butylene, t butylene, amylene, hexylene and 2-ethylhexylene.

The pharmaceutically acceptable nontoxic salts include the organic and inorganic acid addition salts, e.g., those prepared from acids such as hydrochloric, sulfuric, sulfarnic, tartaric, fumaric, hydrobr-omic, hydriodic, glycolic, citric, maleic, phosphoric, succinic, acetic, nitric and the like.

The term (lower)alkyl as used herein means both straight and branched chain alkyl radicals containing from 1 to 8 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, Z-ethylhexyl, etc.

The term (lower)alkenyl as used herein means both straight and branched chain alkenyl radicals containing from 2 to 8 carbon atoms, e g. ethenyl, allyl, l-propenyl, lbutenyl, 3-butenyl, Z-methyl-l-propenyl, 3-penteny1, 1- hexenyl, 7-octenyl, etc.

The term (lower)alkenyl as used herein means both straight and branched chain alkenyl radicals containing from 2 to 8 carbon atoms, e.-g. ethinyl, propargyl, 1- butinyl, Z-butinyl, 1,1-dimethylpropargyl, l-pentinyl, 1- heptinyl, etc.

Similarly, where the term (lower) is used as part of the description of another group, e.g., (lower)alkoxy it refers to the alkyl portion of such group which is therefore as described in connection with (lower) alkyl.

Preferred compounds of the present invention are those having the following formulae VII o wherein R and Y are as represented above.

The compounds of this invention are valuable pharmaceutical agents. They produce a depressant effect on the central nervous system which makes them useful for depressing the central nervous System. The compounds are particularly useful for the depression of spinal transmission, as anticonvulsants for controlling various types of convulsant seizures, and as sedatives.

When, for example, one of the preferred compounds of this invention, {3 diethylaminoethyl 1 oxo- 2a,3,4,S-tetrahydroacenaphthen 2a carboxylate hydrochloride, was administered orally to mice at dosages of 300 mg./kg., the compound protected the mice against both electrically-induced and Metrazol-induced convulsions. When another of the preferred compounds of this invention, 2a-cyano-2a,3,4,5 tetrahydroacenaphthen 1- one, was administered orally to mice at dosages of 300 mg./kg., the compound protected the mice against Metrazol-induced convulsions. When still another of the preferred compounds of this invention, 'y-dimethylaminopropyl-1-oxo-2a,3,4,5-tetrahydroacenaphthen 2a carboxylate hydrochloride, was administered orally to mice at dosages of 300 mg/kg, the compound strongly depressed spinal transmission.

The compounds of the present invention can be compounded and formulated into pharmaceutical preparations for oral or parenteral administration with organic or inorganic solid materials or liquids that are pharmaceutically acceptable carriers. The compositions may take the form of tablets, effervescent tablets, powders, granules, capsules (both hard and soft shell capsules), suspensions, solutions, emulsions, injectable solutions and suspensions and the like. Such compositions are considered within the scope of this invention.

The compounds of the present invention (Formula I) wherein R is cyano, are prepared by the hydrolysis of a compound having the following formula I i l-NH: e

wherein R is as described above, with an alkali metal cyanide, e.g., sodium cyanide. The procedure is generally described by C. F. Koelsch in J. Org. Chem, vol. 25, pp.

4- 2088-2091, and specifically described in Example 1 herein.

The compounds of Formula I wherein R is other than cyano are prepared by the reaction of an acid halide of a compound of the formula l C-OH wherein R R and Y are as described above. The reaction is prefcrably carried out at a low temperature, e.g., 0-20 C.

The compounds of Formula XI are novel intermediates and considered a part of the invention, and are conveniently prepared by the hydrolysis of a compound of Formula IX with a strong mineral acid, preferably aqueous sulfuric acid (535%) at elevated temperature, e.g., heating the reaction on a steam bath for 20 hours. These compounds are then conveniently converted to acid halides by reacting with thionyl chloride.

The starting materials used in the process described herein are compounds which are either commercially available, well-known in the art, or easily prepared in accordance with standard organic procedures previously described in the chemical literature. For example, the preparation of 2-carboxamido-3,4 trimethyleno l indenone (included in Formula X) is described in J. Org. Chem., vol. 26, pp. 4702-4704 and vol. 27, p. 4428 4432.

The compositions of this invention when administered orally or parenterally in an effective amount are effective in depressing the central nervous system.

The following examples are intended to illustrate the invention described herein without unduly restricting it.

Example 1.-Preparation of Z-carboxamido-Za-cyano- 221,3,4,5-tetrahydroacenaphthen-1one O- CONHz Five grams of 2-carboxamido-3,4-trimethyleno-1-indenone, 20 ml. of water, 7 gm. of t-butanol, and 2 gm. of sodium cyanide were placed in a beaker and stirred for 5 minutes while heating gently on the steam bath. A dark red solution resulted which was cooled to 0 C. after standing at room temperature for several hours. The solution was acidified with 20% sulfuric acid to Congo red, and diluted to 250 ml. with water. A yellow precipitate was produced which was collected by filtration, giving 5.5 gm. of crude product, melting at 202-205 C. Several recrystallizations from ethanol gave colorless crystals of 2-carboxamido-Za-cyano-Za,3,4,5-tetrahydroacenaphthen-l-one, having a melting point of 212- 214 C., exhibiting an infrared absorption spectrum in KBr having maxima at the following wavelengths (in microns):

a 2.92;; (NH 4.5 (ON), 5.83 (CO), 6.0;4 (CONH xiii 1P 256 m (e=10,100), and 296 111; (6 2,700)

and having the following elemental analysis:

Analysis.-Calcd. for C H N O C, 69.98%; H, 5.04%; N, 11.75%. Found: C, 70.17%; H, 5.22%; N, 11.78%.

Example 2.Preparation of 2-a-cyano-2a,3,4,5-tetrahydroacenaphthen-l-one A mixture of 1 gm. of 2-carboxamido-Za-cyano-Za,3,4, S-tetrahydroacenaphthen-l-one in 40 ml. of phosphoric acid was heated on the steam bath for 12 hours. The resulting solution was poured into 100 ml. of water, and cooled in the refrigerator. The white solid was collected and extracted with 5% sodium bicarbonate, leaving 0.2 gm. of crude product, having a melting point of 110-112" C. Recrystallization from 95% ethanol gave colorless crystals of 2a-cyano-2a,3,4,5-tetrahydroacenaphthen-l-one, having a melting point of 123l24 C., exhibiting an infrared absorption spectrum in KBr having maxima at the following wavelengths (in microns):

having the following elemental analysis:

Analysis.-Calcd. for C H NO: C, 79.16%; H, 5.62%; N, 7.10%. Found: C, 79.34%; H, 5.68%; N, 8.08%, and having the following molecular weight as determined in CHCl Molecular weight calcd. for C H NO: 197.2. Found: 204.

Example 3.-Preparation of Za-earboxy-Za,3,4,5-tetrahydroacenaphthen-l-one and having the following elemental analysis:

Analysis.Calcd. for C H O C, 72.21%; H, 5.60%.

Found: C, 72.50%; H, 5.86%.

Example 4.-Preparation of fi-diethylaminoethyl l-oxo- 2a,3,4,5 tetrahydroacenaphthen-Za-carboxylate hydrochloride (H) CH2CH3 O C-O-OHzCHa-N CHgOHa A quantity of 5.0 gm. (19 millimols) of Za-carboxy-Za, 3,4,S-tetrahydroacenaphthen-l-one was dissolved in a minimum amount of boiling dry benzene in a 300-ml. roundbottomed three-neck flask, 4.55 gm. (38 millimols) of thionly chloride (distilled from quinoline, then redistilled from linseed oil) was added dropwise over a period of 10 minutes from a pressure equalizing separatory funnel, and the mixture was refluxed on a steam bath for 1 hour. The excess thionyl chloride was removed as an azeotrope with benzene (2 liters of benzene being distilled). The reaction mixture was cooled in an ice bath, and 2.26 gm. (l9 millimols) of Z-diethylaminoethanol was added dropwise over a period of 20 minutes. The mixture was stirred in an ice bath for 1 hour, then at room temperature for 1 hour, the solvent removed by a stream of air; the resulting oil was dissolved in a small amount of n-propyl alcohol and hydrogen chloride bubbled through, yielding 2.7 gm. of a white solid, crude product, having a melting point of 183 C. Recrystallization from isopropanol yielded a white powder, ,B-diethylamin-oethyl 1-oxo-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate hydrochloride having a melting point of 205206 C., exhibiting an infrared absorption spectrum in KBr having maxima at the following wavelengths (in microns):

ALE; 3.38 1 (CH), 3.64 3.87;]. and 4.05;; (NH 5.79 1.

(CO) and 5.90 (00 R) and having the following elemental analysis:

Analysis.Calcd. for C H NO Cl: C, 64.85%; H, 7.45%; Cl, 10.08%. Found: C, 64.95%; H, 7.36%; Cl, 10.18%.

Example 5.Preparation of 'y-dimethylaminopropyl 1- oxo 2a,3,4,5 tetrahydroacenaphthen-Za-carboxylate hydrochloride A quantity of 5.0 gm. (19 millimols) of Za-carboxy-Za, 3,4,5-tetrahydroacenaphthen-l-one was dissolved in a minimum amount of boiling dry benzene in a 300-ml. round-bottomed three-neck flask, 4.55 gm. (38 millimols) of thionyl chloride (distilled from quinoline, then redistilled from linseed oil) was added dropwise over a period of 10 minutes from a pressure equalizing separatory funnel, and the mixture refluxed on a steam bath for 1 hour. The excess thionyl chloride was removed as an azeotrope with benzene (2 liters of benzene being distilled). The reaction mixture was cooled in an ice bath, and 1.99 gm. (l9 millimols) of 3-dimethylaminopropanol was added dropwise over a period of 20 minutes. The mixture was stirred in an ice bath for 1 hour, then at room temperature for 1 hour, the solvent removed by a stream of air; the resulting oil was dissolved in a small amount of npropyl alcohol, and hydrogen chloride bubbled through, yielding 1.3 gm. of a slightly yellowish white powder, crude product, having a melting point of 179-182 C. Recrystallization from isopropanol yielded a white powder, 'y-dimethylaminopropyl 1-oxo-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate hydrochloride, having a melting point of l83l84 C., exhibiting an infrared absorption spectrum in KBr, having maxima at the following wavelengths (in microns):

3.41 (CH), 3.91 1 and 4.09;]. (NH and 5.87

(broad) (CO and 00 R) and having the following elemental analysis:

Analysis.--Calcd. for C H NO Cl: C, 63.99%; H, 7.16%; Cl, 10.09%. Found: C, 63.70%; H, 7.23%; C], 10.68%.

7 Example 6 When, in the procedure of Example 1, 2-carboxon1ido- 3,4-trimethyleno-l-indenone is replaced by an equal molar amount of 2-carboxamido-3,4-trimethyleno-5 -brom0-1-indenone, 2-carboxamido-3,4-trimethyleno-6-chloro-1-indenone, 2-carboxamido-3,4-trimethyleno-S-trifiuoromethyl- 1- indenone, 2-carboxamido-3,4-trirnethyleno-7-methyl-l-indenone, 2-carboxamido-3,4-trimethyleno-5 -ethyl-1-indenone, Z-carhoxamido-3,4-trimethyleno-6-iodo- 1 -indenone, 2-carboxamido-3 ,4-trimethyleno-7-fiuorol-indenone, 2-carboxamido-3,4-trimethyleno-5 -methoxy-1-indenone, 2-carboxamido-3,4-trimethyleno-6-trifiuoromethyl- 1 indenone, 2-carboxamido-3,4-trimethyleno-6-acetyl-l-indenone, 2-carboxamido-3,4-trimethyleno-5-acetoxy- 1 -indenone and Z-carboxamido-3,4-trimethyleno-7-butyl-1-indenone,

there are obtained,

Example 7 When, in the procedure of Example 2, 2-carboxamido- 2a cyano 2a,3,4,S-tetrahydroacenaphthen-l-one is replaced by an equal molar amount of each of the products of Example 6, the following compounds are obtained,

2a-cyano-6-bromo-2a,3,4,5-tetrahydroacenaphthen-1-one, Za-cyanoJ-chloro-Za,3,4,S-tetrahydroacenaphthen-l-one, 2a-cyano-6-trifluoromethyl-2a,3,4,5-tetrahydroacenaphthen-l-one, 2a-cyano-8-methyl-2a,3,4,S-tetrahydroacenaphthen-1- one, 2a-cyano-6-ethyl2a,3,4,S-tetrahydroacenaphthen-l-one, 2a-cyano-7-iodo-2a,3,4,S-tetrahydroacenaphthen-l-one, 2a-cyano-8-fiuoro-2a,3,4,5-tetrahydroacenaphthen-l-one, Za-cyano-6-methoxy-2a,3,4,5-tetrahydroacenaphthen-1- one, 2a-cyano-7-trifiuoromethyl-2a,3,4,5-tetrahydroacenaphthen-l-one, 2a-cyano-7-acetyl-2a,3,4,S-tetrahydroacenaphthen-l-one, 2a-cyan0-6-hydroxy-2a,3,4,S-tetrahydroacenaphthen-1- one, and 2a-cyano-B-butyl-Za,3,4,S-tetrahydroacenaphthen-l-one,

respectively.

Example 8 When, in the procedure of Example 3, 2-carboxamido- 2a cyano 2a,3,4,5 tetrahydroacenaphthen 1 one is replaced by an equal molar amount of each of the products of Example 6, the following compounds are obtained,

2a-carboxy-6-bromo-2a,3,4,5-tetrahydroacenaphthen-1- one, 2a-car-boxy-7-chloro-2a,3,4,5 -tetrahydroacenaphthen-1- one, 2a-carboxy-6-trifiuoromethyl-2a,3,4,S-tetrahydroacenaphthenl-one, Za-carboxy-8-methyl-2a,3,4,5-tetrahydroacenaphthen-1- one, 2a-carboxy-6-ethyl-2a,3,4,5-tetrahydroacenaphthen-l-one, 2a-carboxy-7-iodo-2a,3 ,4,5-tetrahydro acenaphthenl-one, Za-carb oxy-8-fluoro-2a,3,4,5-tetrahydroacenaphthen- 1- one, 2a-carboxy-6-methoxy-2a,3,4,5-tetrahydroacenaphthen-1- one, 2a-carboxy-7-trifiuoromethyl-2a,3 ,4,5-tetrahydroacenaphthen-l-one, 2a-carboxy-7-acetyl-2a,3,4,S-tetrahydroacenaphthen-1- one, 2a-carboxy-6-hydroxy-2a,3,4,S-tetrahydroacenaphthen-1- one, and 2a-carboxy-8-butyl-2a,3 ,4,S-tetrahydroacenaphthenl-one,

respectively.

Example 9 When, in the procedure of Example 4, 2a-carboxy- 2a,3,4,S-tetrahydroacenaphthen-l-one is replaced by an equal molar amount of each of the products of Example 8, the hydrochloride salts of the following compounds are obtained,

fl-diethylaminoethyl 1-oxo-6-bromo-2a,3,4,S-tetrahydro.

acenaphthen-Za-carboxylate,

fi-diethylaminoethyl 1-oxo-7-chloro-2a,3,4,S-tetrahydroacenaphthen-2a-carboxylate,

,B-diethylaminoethyl 1-oxo-8-methyl-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate,

fl-diethylaminoethyl 1-oxo-6-ethyl-2a,3,4,5-tetrahydroacenaphthen-2a-carboxylate,

p-diethylaminoethyl 1-oxo-7-iodo-2a,3,4,i-tetrahydroacenaphthen-Za-carhoxylate,

fi-diethylaminoethyl l-oxo-8-fiuoro-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate,

fl-diethylaminoethyl l-oxo-6-methoxy-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate,

fi-diethylaminoethyl 1-oxo-7-triflu0romethyl-2a,3,4,5-

tetrahydroacenaphthen-Za-carboxy-late,

fl-diethylaminoethyl 1-oxo-7-acetyl-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate,

fl-diethylaminoethyl 1-ox0-6-hydroxy-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate and fl-diethylaminoethyl 1-oxo-8-butyl-2a,3,4,5-tetrahydro.

acenaphthen-2-carboxylate, respectively.

Example 10 When, in the procedure of Example 5, Za-carboxy- 2a,3,4,5-tetrahydroacenaphthen-l-one is replaced by an equal molar amount of each of the products of Example 8, the hydrochloride salts of the fol-lowing compounds are obtained,

'y-dimethylaminopropyl 1-oxo-6-bromo2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate, 'y-dimethylaminopropyl 1-oxo-7-chloro-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate, -dimethylaminopropyl 1-oxo-6-trifluoromethyl-2a,3,4,5.

tetrahydroacenaphthen-2a-carboxylate, 'y-dimethylaminopropyl 1-oxo-8-methy-l-2a,3,4,5-tetrahydroacenaphthen-2a-carboxylate, 'y-dimethylaminopropyl 1-oxo-6-ethyl-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate, 'y-dirnethylarninopropyl 1-oxo-7-iodo-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate, -dimethylaminopropyl 1-oxo-8-fluoro-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate, 'y-dimethylaminopropyl 1-oxo-6-methoxy-2a,3,4,5-tetrahydroacenaphthen-Za-carboxylate,

l l 3. The compound having the formula O C 1120 H CHzCH;

1 2 4. The compound having the formula O OH m n COCH2CHzCHz-N 5 C II:

10 References Cited UNITED STATES PATENTS 2,589,934 3/1952 Glenn et a1. 260247.7

CHARLES B. PARKER, Primary Examiner.

D. H. TORRENCE, Assistant Examiner. 

